Abstract
Antibody-drug conjugates (ADCs) represent a promising modality for the treatment of cancer. The therapeutic strategy is to deliver a potent drug preferentially to the tumor and not normal tissues by attaching the drug to an antibody that recognizes a tumor antigen. The selection of antigen targets is critical to enabling a therapeutic window for the ADC and has proven to be surprisingly complex. We surveyed the tumor and normal tissue expression profiles of the targets of ADCs currently in clinical development. Our analysis demonstrates a surprisingly broad range of expression profiles and the inability to formalize any optimal parameters for an ADC target. In this context, we discuss additional considerations for ADC target selection, including interdependencies among biophysical properties of the drug, biological functions of the target and strategies for clinical development. The TPBG (5T4) oncofetal antigen and the anti-TPBG ADC A1-mcMMAF are highlighted to demonstrate the relevance of the target’s biological function. Emerging platform technologies and novel biological insights are expanding ADC target space and transforming strategies for target selection.
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Abbreviations
- ADC:
-
Antibody-drug conjugate
- ALCL:
-
Anaplastic large-cell lymphoma
- APEX:
-
Absolute Protein Expression Measurements
- BRCA:
-
Breast invasive carcinoma
- CCLE:
-
Cancer Cell Line Encyclopedia
- CD:
-
Cluster of Differentiation
- CEACAM:
-
Carcinoembryonal antigen
- COAD:
-
Colon adenocarcinoma
- CSC:
-
Cancer stem cell
- DLBC:
-
Diffuse large B-cell lymphoma
- DLT:
-
Dose-limiting toxicity
- EBV:
-
Epstein-Barr Virus
- EGFR:
-
Epidermal growth factor receptor
- EMT:
-
Epithelial-mesenchymal transition
- ERBB2:
-
erb-b2 receptor tyrosine kinase 2 (also known as HER2)
- G2/M:
-
Gap2 / mitosis
- GPI:
-
Glycosylphosphatidylinositol
- GTEx:
-
Genotype-Tissue Expression database
- HL:
-
Hodgkin’s lymphoma
- HSC:
-
Hematopoietic stem cell
- iBAQ:
-
Intensity-Based Absolute Quantification
- KIRC:
-
Kidney renal clear cell carcinoma
- LAML:
-
Acute myeloid leukemia
- LUAD:
-
Lung adenocarcinoma
- LUSC:
-
Lung squamous cell carcinoma
- mAb:
-
Monoclonal antibody
- MESO:
-
Mesothelioma
- MMAF:
-
Monomethylauristatin F
- MTI:
-
Microtubule inhibitor
- NSCLC:
-
Non-small cell lung cancer
- OV:
-
Ovarian serous cystadenocarcinoma
- PAAD:
-
Pancreatic adenocarcinoma
- PDX:
-
Patient-derived xenograft
- PRAD:
-
Prostate adenocarcinoma
- PSMA:
-
Prostate-specific membrane antigen (also known as FOLH1)
- RPKM:
-
Reads per kilobase per million
- SKCM:
-
Skin Cutaneous Melanoma
- TCGA:
-
The Cancer Genome Atlas
- T-DM1:
-
Trastuzumab emtansine
- TIC:
-
Tumor-initiating cell
- TMDD:
-
Target-mediated drug disposition
- TPBG:
-
Trophoblast glycoprotein (also known as 5T4)
- TPM:
-
Transcripts per million
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The authors thank Eugene Melamud for assistance with the proteomics data analysis and Chris O’Donnell, Hans Peter Gerber, Kenneth Geles, Paul Rejto and Jeremy Barton for comments on the manuscript.
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Damelin, M., Zhong, W., Myers, J. et al. Evolving Strategies for Target Selection for Antibody-Drug Conjugates. Pharm Res 32, 3494–3507 (2015). https://doi.org/10.1007/s11095-015-1624-3
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DOI: https://doi.org/10.1007/s11095-015-1624-3